Cardiac pacing using adjustable atrio-ventricular delays

ABSTRACT

A pacing system for providing optimal hemodynamic cardiac function for parameters such as contractility (peak left ventricle pressure change during systole or LV+dp/dt), or stroke volume (aortic pulse pressure) using system for calculating atrio-ventricular delays for optimal timing of a ventricular pacing pulse. The system providing an option for near optimal pacing of multiple hemodynamic parameters. The system deriving the proper timing using electrical or mechanical events having a predictable relationship with an optimal ventricular pacing timing signal.

CROSS REFERENCE TO RELATED APPLICATIONS

This application is a continuation of U.S. patent application Ser. No.10/243,811, filed on Sep. 13, 2002, now U.S. Pat. No. 6,684,103, whichis a continuation of U.S. patent application Ser. No. 10/008,830, filedon Dec. 7, 2001, now issued as U.S. Pat. No. 6,542,775, which is acontinuation of U.S. patent application Ser. No. 09/661,608, filed onSep. 14, 2000, now issued as U.S. Pat. No. 6,351,673, which is acontinuation of U.S. patent application Ser. No. 09/492,911, filed onJan. 20, 2000, now issued as U.S. Pat. No. 6,360,127, which is acontinuation of U.S. patent application Ser. No. 09/075,278, filed May8, 1998, now issued as U.S. Pat. No. 6,144,880, the specifications ofwhich are incorporated herein by reference.

FIELD OF THE INVENTION

The present invention relates generally to a method and apparatus forcardiac pacing and, in particular, to a pacing system providingadjustable atrio-ventricular time delays to improve different heartperformance parameters.

BACKGROUND OF THE INVENTION

The heart is the center of the circulatory system. It is an organ whichperforms two major pumping functions and may be divided into right andleft heart “pumps.” The left heart pump draws oxygenated blood from thelungs and pumps it to the organs of the body. The right heart pump drawsblood from the body organs and pumps it into the lungs. For a humanheart, the right heart pump is on a patient's right side and the leftheart pump is on the patient's left side. Figures in this document, suchas FIG. 1, show a “top” view of the heart, which is the view that aphysician observes during open heart surgery. Therefore, the left heartpump is on the right hand side of the FIG. 1 and the right heart pump ison the left hand side of FIG. 1. Each heart pump includes an upperchamber called an atrium and a lower chamber called a ventricle. Theleft heart pump therefore contains a left atrium (LA) and a leftventricle (LV), separated by a valve called the mitral valve. The rightheart pump contains a right atrium (RA) and a right ventricle (RV),separated by a valve called the tricuspid valve.

The blood flows in the circulatory system in the following path: fromthe peripheral venous system (blood which has transferred through thebody organs) to the RA, from the RA to the RV through the tricuspidvalve, from RV to the pulmonary artery through the pulmonary valve, tothe lungs. Oxygenated blood from the lungs is drawn from the pulmonaryvein to the LA, from the LA to the LV through the mitral valve, andfinally, from the LV to the peripheral arterial system (transferringblood to the organs of the body) through the aortic valve.

Normally, the heart pumps operate in synchrony and ensure the properpumping action to provide oxygenated blood from the lungs to the organsof the body. A normal heart provides this synchrony by a complexconduction system which propagates electrical pulses to the heart muscletissue to perform the necessary atrial and ventricular contractions. Aheartbeat is the result of a regular train of electrical pulses to theproper portions of the heart to provide rhythmic heart pumping. Theheart muscle provides pumping by the contraction of muscle tissue uponreceipt of an electrical signal, and the pumping action is made possiblethrough a system of heart valves which enable blood flow in a singledirection. Thus, the heart includes a complex electrical and mechanicalnetwork.

To pump blood through the circulatory system, a beating heart performs acardiac cycle. A cardiac cycle consists of a systolic phase and adiastolic phase. During systole, the ventricular muscle cells contractto pump blood through both the pulmonary circulation and the systemiccirculation. During diastole, the ventricular muscle cells relax, whichcauses pressure in the ventricles to fall below that in the atria, andthe ventricles begin to be refilled with blood.

In normal condition, the cardiac pumping is highly efficient. One aspectof this high efficiency is due to sequential atrio-ventricularcontraction. Near the end of diastole, the atria contract, causing anextra amount of blood to be forced into the ventricles. Thus, theventricles have more blood (preload) to pump out during next systole.Another aspect of this high efficiency in blood pumping is contributedfrom a network or fast ventricular conduction system. As shown in FIG.1, the system includes right and left bundle branches of conductivetissues that extend from the Bundle of His and the massive network offast conducting Purkinje fibers that cover most of the endocardialsurface of the ventricles. Electrical signals coming from the atrium arerelayed to the Purkinje fibers through the bundle branches, and to thedifferent regions of the ventricles by the Purkinje fiber network.Therefore the entire ventricular muscle cells can contract synchronouslyduring systole. This synchronized contraction enhances the strength ofthe pumping power.

To assess the cardiac function, it is important to examine the LVsystolic performance which directly determines the ability of the heartto pump blood through the systemic circulation. There are multiple waysto assess the performance of the heart. One way is to examine how wellthe LV contracts in order to determine the effectiveness of the LV as apump. As can be seen from FIG. 2, the LV starts to contract after anelectrical signal propagating down the left bundle branches stimulatesmuscle cells of septal wall M and lateral wall N. In FIG. 3, the walls Mand N are contracting such that they are forced towards each other topump blood out of the ventricle. One measure of LV contractioneffectiveness is called “contractility.” Left ventricular contractilityis a measure of overall strength of the contracting power of the LVmuscle cells. It is a function of the health of the LV muscle tissue andthe coordination of the contractions of the entire LV, including walls Mand N. Such coordination depends on the health of the left bundlebranches and on the health of the fast conducting Purkinje fibernetwork. LV contractility is estimated by measuring the peak positiverate of change of the LV pressure during systole. In mathematical terms,this is the maximum positive derivative of the LV pressure, which isdenoted by the term “LV+dp/dt”.

LV systolic performance is also measured by stroke volume, which is thevolume of blood pumped out of the LV per systole. Stroke volume can beestimated by measuring aortic pulse pressure (PP).

Cardiac muscle cells need to be electrically excited before they canhave a mechanical contraction. During the excitation (depolarization),electrical signals will be generated and they can be recorded bothintracardially and extracardially. The recorded signals are generallycalled electrocardiogram (ECG). An ECG recorded intracardially is alsocalled an electrogram, which is recorded from an electrode placedendocardially or epicardially in an atrium or a ventricle. An ECGrecorded extracardially is often called surface ECG, because it isusually recorded from two or more electrodes attached to the skin of thebody. A complete surface ECG recording is from 12-lead configuration.

The features in ECG are labeled according to the origin of theelectrical activity. The signals corresponding to intrinsicdepolarization in an atrium and a ventricle are called P-wave and QRScomplex, respectively. The QRS complex itself consists of a Q-wave, aR-wave, and a S-wave. The time interval from P-wave to R-wave is calledPR interval. It is a measure of the delay between the electricalexcitation in the atrium and in the ventricle.

Several disorders of the heart have been studied which prevent the heartfrom operating normally. One such disorder is from degeneration of theLV conduction system, which blocks the propagation of electric signalsthrough some or all of the fast conducting Purkinje fiber network.Portions of the LV that do not receive exciting signals through the fastconducting Purkinje fiber network can only be excited through muscletissue conduction, which is slow and in sequential manner. As a result,the contraction of these portions of the LV occurs in stages, ratherthan synchronously. For example, if the wall N is affected by theconduction disorder, then it contracts later than the wall M which isactivated through normal conduction. Such asynchronous contraction ofthe LV walls degrades the contractility (pumping power) of the LV andreduces the LV+dp/dt (maximum positive derivative of the LV pressure) aswell.

Another disorder of the heart is when blood in the LV flows back intothe LA, resulting in reduced stroke volume and cardiac output. Thisdisorder is called mitral regurgitation and can be caused by aninsufficiency of the mitral valve, a dialated heart chamber, or anabnormal relationship between LV pressure and LA pressure. The amount ofthe back flow is a complex function of the condition of the mitralvalve, the pressure in the LV and in the LA, and the rate of blood flowthrough the left heart pump.

These disorders may be found separately or in combination in patients.For example, both disorders are found in patients exhibiting congestiveheart failure (CHF). Congestive heart failure (CHF) is a disorder of thecardiovascular system. Generally, CHF refers to a cardiovascularcondition in which abnormal circulatory congestion exists as a result ofheart failure. Circulatory congestion is a state in which there is anincrease in blood volume in the heart but a decrease in the strokevolume. Reduced cardiac output can be due to several disorders,including mitral regurgitation (a back flow of blood from the LV to theLA) and intrinsic ventricular conduction disorder (asynchronouscontraction of the ventricular muscle cells), which are the two commonabnormalities among CHF patients.

Patients having cardiac disorders may receive benefits from cardiacpacing. For example, a pacing system may offer a pacing which improvesLV contractility, (positive LV pressure change during systole), orstroke volume (aortic pulse pressure), however, known systems requirecomplicated measurements and fail to provide automatic optimization ofthese cardiac performance parameters. Furthermore, the measurements arepatient-specific and require substantial monitoring and calibration foroperation. Therefore, there is a need in the art for a system which maybe easily adapted for optimizing various cardiac parameters, including,but not limited to, LV contractility, (peak positive LV pressure changeduring systole, LV+dp/dt), and cardiac stroke volume (pulse pressure).The system should be easy to program and operate using straightforwardpatient-specific measurements.

SUMMARY OF THE INVENTION

This patent application describes multiple ways to provide optimizedtiming for ventricular pacing by determining certain intrinsicelectrical or mechanical events in the atria or ventricles that have apredictable timing relationship to the delivery of optimally timedventricular pacing that maximizes ventricular performance. Thisrelationship allows prediction of an atrio-ventricular delay used indelivery of a ventricular pacing pulse relative to a sensed electricalP-wave of the atrium to establish the optimal pacing timing. Alsoprovided are embodiments for measuring these events and deriving thetiming relationship above. Those skilled in the art will understand uponreading the description that other events may be used without departingfrom the present invention.

In several embodiments, these measurements are used to optimizeventricular contractility as measured by maximum rate of pressure changeduring systole. In other embodiments, these measurements are used tooptimize stroke volume as measured by aortic pulse pressure. In otherembodiments, a compromise timing of pacing is available to providenearly optimal improvements in both peak positive pressure change duringsystole and aortic pulse pressure. In one embodiment, this pacing isprovided by adjusting the atrio-ventricular delay time interval, whichis the time interval after a sensed P-wave, to deliver a pacing pulse toachieve the desired cardiac parameter optimization.

This summary of the invention is intended not to limit the claimedsubject matter, and the scope of the invention is defined by attachedclaims and their equivalents.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 is a diagram of a heart showing the chambers and the nervousconduction system.

FIG. 2 is a diagram of a ventricle beginning contraction.

FIG. 3 is a diagram of a contracted ventricle.

FIG. 4A is a graph of left ventricle intrinsic pressure as a function oftime as referenced to an intrinsic P-wave event.

FIG. 4B is a graph of left ventricle intrinsic electrogram as a functionof time as referenced to an intrinsic P-wave event.

FIG. 4C is a timing diagram showing a marker of an intrinsic P-wave andthe marker of a ventricular pacing pulse that is optimally timed formaximum LV contractility as referenced to a paced P-wave event;

FIG. 4D is a graph of left atrial intrinsic pressure as a function oftime as referenced to an intrinsic P-wave event.

FIG. 4E is a timing diagram showing a marker of an intrinsic P-wave andthe marker of a ventricular pacing pulse that is optimally timed formaximum stroke volume as referenced to a paced P-wave event.

FIG. 5 is a flow diagram for detection of a Q* event.

FIG. 6 shows embodiments of the apparatus for the present subjectmatter.

FIG. 7 shows an embodiment of a predetermined mapping according to thepresent subject matter.

DETAILED DESCRIPTION

In the following detailed description, reference is made to theaccompanying drawings which form a part hereof and in which is shown byway of illustration specific embodiments in which the invention can bepracticed. These embodiments are described in sufficient detail toenable those skilled in the art to practice and use the invention, andit is to be understood that other embodiments may be utilized and thatelectrical, logical, and structural changes may be made withoutdeparting from the spirit and scope of the present invention. Thefollowing detailed description is, therefore, not to be taken in alimiting sense and the scope of the present invention is defined by theappended claims and their equivalents.

Some of the embodiments illustrated herein are demonstrated in animplantable cardiac pacemaker, which may include numerous pacing modesknown in the art. However, these embodiments are illustrative of some ofthe applications of the present system, and are not intended in anexhaustive or exclusive sense. For example, the present system issuitable for implementation in a variety of implantable and externaldevices.

The present system provides a means for optimizing cardiac systolicfunction based on different cardiac performance measurements. Thepresent disclosure provides a number of embodiments useful for, amongother things, optimizing cardiac pumping strength and stroke volume. Theconcepts described herein may be used in a variety of applications whichwill be readily appreciated by those skilled in the art upon reading andunderstanding this description. The cardiac performance measurementsexpressly provided herein include contractility, peak positiveventricular pressure change, stroke volume, and pulse pressure. Othercardiac performance may be maximized using the teachings providedherein, and therefore, the express teachings of this disclosure are notintended in an exclusive or limiting sense. These concepts are expresslydescribed in terms of the left ventricle, however, applications to otherchambers of the heart, including the right ventricle, may be readilyappreciated by those skilled in the art without departing from thepresent invention.

The inventors of this subject matter performed numerous tests andexperiments to develop a pacing system which may be used to treatcardiac disorders. The system includes method and apparatus which areuseful for providing optimization of different cardiac performanceparameters, including, but not limited to, ventricular contractility,maximum rate of pressure change during systole, stroke volume, and pulsepressure. The embodiments provided herein use right atrial (RA) sensingevents to time the pacing of the left ventricle (LV), right ventricle(RV), or both (BV) to optimize cardiac performance parameters. However,it is understood that these teachings are applicable to other pacingconfigurations. The teachings herein provide, among other things,optimal pacing which is selectable for treating different cardiacdisorders. The disorders include, but are not limited to, congestiveheart failure (CHF), mitral regurgitation, and ventricular conductiondisorder. The optimal pacing taught herein includes embodiments which donot use patient-specific measurements of hemodynamic parameters, such aspressure, blood flow, or measurements not typically provided byimplantable pacing devices, and the system is capable of automaticadjustment to meet the needs of a particular patient.

AVD Time Intervals

Implantable rhythm management devices such as pacemakers, are useful fortreating patients with abnormal cardiac functions. One pacing therapy iscalled DDD pacing mode. In DDD pacing mode, pacing electrodes are placedin the atrium (for example, the RA) and one or both of the ventricles.These electrodes are also used to sense electric signals from the atriumand the ventricle(s). If the device senses a signal in the atrium, itwill inhibit the delivery of a pacing pulse to the atrium, otherwise itwill pace the atrium after the end of a predetermined time period.Whenever the device senses or paces the atrium, it generates an eventmarker and at the same time starts an atrio-ventricular delay (AVD) timeinterval. At the end of this delay interval, the device will pace theventricle(s) if no signals from the ventricle(s) are sensed by thedevice. Systems which provide ventricular pacing signals relative to theP-wave of an electrocardiogram signal refer to atrio-ventricular timedelay interval (AVD time interval) as the time delay from the sensedP-wave to the delivery of the ventricular pacing signal. In patientsexhibiting ventricular conduction disorder, such as the CHF condition,therapy using an AVD time interval which is shorter than the PR timeinterval may provide improved contractility because patients withdegeneration of their LV conduction system require pacing of theaffected parts of the LV (for example, the lateral wall N) early enoughso that the contraction may be in phase with other parts of the LV thatare excited by intrinsic conduction (for example wall M). Properly timedventricular pacing can make both walls M and N contract in phase forincreased contractility.

Patients with decreased stroke volume benefit from a shorter AVD timeinterval to decrease the mitral regurgitation effects and increaseaortic pulse pressure. In addition, for congestive heart failure (CHF)patients, their PR interval may be prolonged which reduces the AVsynchrony to some extent. Such a reduction in AV synchrony may furtherincrease mitral regurgitation, and reduce the effect of preload of theLV. Use of a shorter AVD time interval increases pulse pressure byforcing the contraction of the LV into an earlier period, thus reducingthe effects of mitral regurgitation.

Optimization of Cardiac Ventricle Contractility and Maximum LeftVentricle Pressure Change During Systole

Left ventricle contractility (pumping power) and peak positive rate ofchange of left ventricle pressure during systole (abbreviated as“LV+dp/dt”) are related cardiac performance parameters. For instance,increases in LV contractility are observed in measurements as increasesin left ventricle pressure change during systole.

FIG. 4A shows an intrinsic or unpaced left ventricle pressure curvefollowing a P-wave. The Y event is the onset of intrinsic LV pressureincrease. FIG. 4B shows an intrinsic left ventricular electrogram whichis a QRS complex following a P-wave. Q* is an electrical signal whichoccurs at the beginning of a QRS complex. R is the largest peak of theQRS complex. In FIG. 4B, the Q* event leads the Y event of FIG. 4A. FIG.4C shows a timing diagram under an optimally paced condition in whichthe LV contractility is maximized. The AVD_(c) time interval is equal tothe time between the P-wave marker and the ventricular pacing marker Vand that pacing provides maximum LV contractility. It is thereforecalled an optimal atrio-ventricular delay for contractility. It is notedthat in the FIG. 4C the P_(p) marker is from a paced condition, asopposed to the P₁ markers in FIGS. 4A and 4B, which arise from intrinsicheart activity. Therefore P_(p) occurs at a different time than P₁.Additionally, the diagrams are not to scale.

In their experimentation, the inventors learned that when pacing formaximum contractility the Q*, Y, and R events had a relativelypredictable timing relationship with respect to the V pacing signal thatis optimally timed by AVD_(c). Furthermore, the inventors learned thatlinear models could be created which map the PQ* interval (the timedifference between a P event and a Q* event) to an optimalatrio-ventricular delay for maximum contractility, AVD_(c) (FIG. 7showing one embodiment). Additionally, linear mappings are possible forPY and PR to AVD_(c), however, each mapping may result in differentcoefficients.

In one embodiment, an intrinsic PQ* time interval is measured for apatient. This is the time interval between the P-wave and a Q* eventwhen no pacing signal is applied. After the PQ* time interval isrecorded and averaged, then a pacing signal is applied with varyingatrio-ventricular delays while monitoring LV+dp/dt (peak positive leftventricular pressure change). Then the atrio-ventricular delay whichproduced the maximum LV+dp/dt (optimal contractility) is determined andnamed as AVD_(c), and is paired with that patient's PQ* time interval.The PQ*, AVD_(c) pairs are generated for a number of other patients andthe data are plotted. In one embodiment, a linear regression method isapplied to determine a straight line approximation for AVD_(c) as afunction of PQ*. The equation is: AVD_(c)=K1 (PQ*)−K2. A programmabledevice which measures the intrinsic PQ* interval can estimate AVDC usingthis equation. Therefore, once K1 and K2 are determined, the calibrationof the device is complete. This means that subsequent patients may haveoptimal contractility pacing without requiring the pressure measurementsand additional calibration stages. As described below, the sameprocedures may be used with PY or PR, however, as stated before, thecoefficients may be different.

This means that, if PQ* is measured, then a patient may receive optimalcontractility pacing of the left ventricle using measurements of theP-wave and of Q*. In the case where PY is used instead of PQ*, then themeasurements will be of the P-wave and of the Y event, which is theonset of pressure increase in the left ventricular contraction. If thePR interval is used, then the measurements will be the P-wave and theR-wave of the QRS complex.

Therefore, given a patient's intrinsic PQ* or PY or PR time interval andthe respective mapping, an AVD_(c) is calculated. This AVD_(c) is anapproximation of the actual AVD_(c) using the mapping method.

It is noted that any event which is relatively constant with respect tothe optimally timed V pacing signal (pacing using AVD_(c)) may be usedas a predictable event for use in the present system. In one embodiment,an event which is relatively constant is one which has a deviationbetween the lesser of 20 ms or 25 percent of the population mean.Therefore, other embodiments incorporating events not expresslymentioned herein may be used without departing from the present system.

P-Wave Signal

When the electronic P-wave signal is used as a reference for any of theembodiments, the P-wave signal is detectable using devices including,but not limited to, catheters or external probes to createelectrocardiograms. In one embodiment, the P-wave is sensed from theright atrium and used as a reference for the time interval measurementsand pacing delivery. In some cases where a patient's atrium is pacedthen the P-wave pacing marker is used instead of the intrinsic P-wave.

PQ* Measurement and Mapping

As stated above, the inventors determined some “events” would have apredictable relationship to the optimally timed ventricular pacingsignal. The Q* event was defined as one candidate because it isrelatively constant relative to the LV pacing mark, V, at optimal timingfor maximum contractility. Q* is an electrical signal which occurs atthe beginning of a QRS complex. Therefore, in one embodiment of thesystem, the time delay between the P-wave and the Q* event is used toprovide the linear variable to calculate AVD_(c). In this embodiment,the equation is: AVD_(c)=K1 (PQ*)−K2.

Furthermore, the inventors of the present system realized that the PQ*interval provides a linear variable which may be used to estimateAVD_(c) using a single calibration procedure for determining theconstants K1 and K2. One type of calibration was discussed above,mapping AVD_(c), PQ* pairs in a linear fashion to provide K1 and K2. ThePQ* and AVD_(c) information is then plotted on a two-dimensional chartand a linear regression method is performed to provide a best line fitthrough the sample point pairs. This linear fit provides the K1 and K2coefficients.

In one study using 13 patients, an equation for AVD_(c) was generatedwhich provided K1 equal to 0.94 and K2 equal to 55.7 milliseconds. Inthis equation, PQ* is measured in milliseconds. This equation isexpressed as: AVD_(c)=0.94 PQ*−55.7 milliseconds. It is noted that thecoefficients may vary and that estimated AVD_(c) may depart from theactual optimum AVD_(c) by approximately 20 percent and continue toprovide near optimal performance within 80 percent of the maximumcontractility. Furthermore, the coefficients may vary slightly dependingon the number of samples taken in the calibration stage. Therefore, thecoefficients provided herein may vary without departing from the presentinvention.

In one embodiment, the P-wave was detected using a threshold detectorwhich indicated a P-wave at approximately 20 percent of the maximumP-wave amplitude in the right atrium. In one embodiment shown in FIG. 5,the Q* event is determined by passing the QRS complex as sampled fromthe left ventricle through a 5 point low-pass digital filter having asampling time of 2 milliseconds, detecting the Q portion of the wave,calculating a maximum absolute value of the slope for the Q-wave, andindicating a point on the filtered Q-wave where the absolute value ofthe slope equals 2% of the absolute value slope of the Q-wave. Thoseskilled in the art will readily recognize that other determinationmethods may be used for P and Q* which do not depart from the presentsystem. Changes in the measurement techniques and slope criteria do notdepart from the present system.

In another embodiment, the coefficient of PQ*, K1, is assumed to beunity, and the coefficient K2 amounts to an offset time delay from thePQ* interval to predict or estimate the optimal AVD_(c). In thisembodiment, PQ* and AVD_(c) are sampled for a variety of patients at avariety of PQ* intervals and a variety of AVD_(c) to generate a meanoffset time delay K2 for a number of patients. In this embodiment, theequation is as follows: AVD_(c) estimated=PQ*−Wa milliseconds. Using theprevious data for the 13 patients, the equation is: AVD_(c)estimated=PQ*−67 milliseconds. This embodiment provides an easiercalculation, since a subtraction is less processor intensive thanmultiplications using floating point numbers. However, some accuracy islost for the approximation.

It is noted that the coefficients may vary and that the estimatedAVD_(c) may depart from the actual optimum AVD_(c) by approximately 20percent and continue to provide near optimal performance within 80percent of the maximum contractility. Furthermore, the coefficients mayvary slightly depending on the number of samples taken in thecalibration stage. Therefore, the coefficients provided herein may varywithout departing from the present invention.

Those skilled in the art will readily recognize that other methods maybe employed to generate other fits to the data which do not depart fromthe scope of the present invention.

In one embodiment, the measurements of the P-wave and Q* are providedusing an electrode implanted in the right atrium and an electrodeimplanted in the left ventricle. A programmable pulse generator is usedto sense the P-wave and measure the time between occurrence of a sensedP-wave and a sensed Q* event. The Q* event is determined by electronicsin the pulse generator which perform the required slope and comparisonoperations to determine Q*. After a PQ* time interval is determined, theAVD_(c) is determined using any of the embodiments described herein andtheir equivalents. Once the AVD_(c) is determined, it may be used in thenext pacing interval to provide an optimized atrio-ventricular delaybased on the PQ* time interval.

It is understood that the Q* event may be defined differently andprovide substantially the same results with a different set ofparameters, K1 and K2. Furthermore, any electrical signal event whichbears a predictable relationship to the beginning of intrinsic LVelectrogram signals may be used in place of Q*. For example, in oneembodiment the beginning of the RV electrogram may be used in place ofQ*. Or in another embodiment, the Q* may be measured by surface ECG asthe onset of the signal averaged QRS complex. Furthermore, informationfrom more than one lead may be used to more accurately determine Q*.

PR Measurement and Mapping

In another embodiment, the R-wave peak, which is the largest peak of theQRS complex of an intrinsic LV electrogram, is used since it has apredictable relationship to the delivery of optimally timed ventricularpacing for maximum contractility. In particular, the linear timerelationship may be derived in terms of the PR interval for optimalatrio-ventricular delay for optimal left ventricular pressure changeduring systole. In this case, the equation is: AVD_(c)=N1 PR−N2, whereAVD_(c) is for pacing the LV, and PR is the time interval from rightatrial sensing marker to the largest peak of the QRS complex ofintrinsic LV electrogram. In one embodiment, the N1 and N2 coefficientsare determined by mapping the PR time interval to the optimal AVD_(c)for a number of patients for optimal left ventricular pressure changeduring systole. In one study using 13 patients, the coefficient N1 isequal to 0.82 and the coefficient N2 is equal to 112 milliseconds. Theequation for this calibration is: AVD_(c)=0.82 PR−112 milliseconds. Itis noted that the coefficients may vary and that the estimated AVD_(c)may depart from the actual optimum AVD_(c) by approximately 20 percentand continue to provide near optimal performance within 80 percent ofthe maximum contractility. Furthermore, the coefficients may varyslightly depending on the number of samples taken in the calibrationstage. Therefore, the coefficients provided herein may vary withoutdeparting from the present invention.

In another embodiment, the N1 coefficient is assumed to be unity, andthe PR, AVD_(c) data pairs are averaged to provide a linear dependencewith an offset equal to N2. This embodiment provides an easiercalculation, since a subtraction is less processor intensive thanmultiplications using floating point numbers. However, some accuracy islost for the approximation. For example, using data in the previousstudy: AVD_(c)=PR−159 milliseconds. In one embodiment, the R-wave signalis measured by detecting the largest peak of the QRS complex of theintrinsic LV electrogram. Therefore, electrical signals are used in thisembodiment to provide the PR time interval, and therefore the optimalatrio-ventricular delay for optimal left ventricular pressure changeduring systole. The coefficients N1 and N2 are provided in an initialcalibration stage, which means that subsequent readings using thisembodiment generate the optimal AVD_(c) automatically upon detection ofthe PR time interval. Furthermore, the N1 and N2 variables may change invalue without departing from the teachings provided herein.

Other features of the QRS complex may be used for measurement. As statedabove, these events may be used as long as they have a predictabletiming relationship to the delivered pacing for optimal contractility.It is noted that the coefficients may vary and that the estimatedAVD_(c) may depart from the actual optimum AVD_(c) by approximately 20percent and continue to provide near optimal performance within 80percent of the maximum contractility. Furthermore, the coefficients mayvary slightly depending on the number of samples taken in thecalibration stage. Therefore, the coefficients provided herein may varywithout departing from the present invention.

PY Measurements and Mappings

In another embodiment, a mechanical event is provided as a referenceinstead of an electrical event. In one embodiment, the mechanical event,Y is determined as the beginning of intrinsic LV pressure development.This means that a pressure transducer such as a micromonometer canprovide instantaneous pressure data in the left ventricle. In thisembodiment, the atrio-ventricular delay optimized for maximum leftventricular pressure change during systole is provided as: AVD_(c)≈M1PY−M2. In one embodiment, a micromonometer is placed in the LV tomeasure left ventricular pressure change during systole. The PY timeinterval, which is the time interval from right atrial sensing of theP-wave to the beginning of the intrinsic LV pressure development, ismapped to recorded AVD_(c) values for maximum left ventricular pressurechange during systole. This mapping is plotted to perform a linearregression in order to determine the coefficients M1 and M2. In onestudy, M1 is equal to 0.96 and M2 is equal to 139 milliseconds.Therefore, in this study, the AVD_(c)=0.96 PY−139 milliseconds. It isnoted that the coefficients may vary and that the estimated AVD_(c) maydepart from the actual optimum AVD_(c) by approximately 20 percent andcontinue to provide near optimal performance within 80 percent of themaximum contractility. Furthermore, the coefficients may vary slightlydepending on the number of samples taken in the calibration stage.Therefore, the coefficients provided herein may vary without departingfrom the present invention.

In another embodiment, the M1 coefficient is approximated as unity, andthen the PY and AVD_(c) pairs are used to determine a linearized mappingwhich amounts to: AVD_(c)=PY−N_(a), where N_(a) is an averaged offsetdelay for the samples taken. In one embodiment, AVD_(c)=PY−150milliseconds. This embodiment provides an easier calculation, since asubtraction is less processor intensive than multiplications usingfloating point numbers. However, some accuracy is lost for theapproximation. Again, it is noted that the coefficients may vary andthat the estimated AVD_(c) may depart from the actual optimum AVD_(c) byapproximately 20 percent and continue to provide near optimalperformance within 80 percent of the maximum contractility. Furthermore,the coefficients may vary slightly depending on the number of samplestaken in the calibration stage. Therefore, the coefficients providedherein may vary without departing from the present invention.

Other mechanical events may be used as long as they are relativelypredictable with respect to the Y event. The Y events may be selectedfrom signals including, but not limited to, ventricular pressure,cardiac phonogram, cardiac acoustic signals (such as recorded from anaccelerometer external to or inside an implantable device), Dopplerrecording of atrio-ventricular valve motion, and M-mode, 2D, or 3D echoimaging of ventricular wall motion (FIG. 6 showing one embodiment of themechanical event sensor).

Stroke Volume Optimization Using Atrio-Ventricular Delay

Stroke volume is related to pulse pressure. The inventors discoveredthat for maximum pulse pressure (stroke volume), there is a predictabletiming relationship between an optimally delivered ventricular pulse Vand the peak of left atrial systole, X. Therefore, the optimalatrio-ventricular delay for maximum pulse pressure, AVD_(s), isdetermined by PX time interval measurements, as shown in FIG. 4E.

In one embodiment, stroke volume is optimized by determining theatrio-ventricular delay for maximum aortic pulse pressure, AVD_(s). Inone embodiment, the X event is measured by placing a pressure sensingcatheter inside the LA. In another embodiment, the X event is detectedby measuring the LV pressure, because the LA contraction is seen in theLV pressure curve by a pre-systolic component. The peak of the LAsystole is considered the same as the pre-systolic pressure in the LVpressure curve. The time interval between P and the pre-systoliccomponent of LV pressure provides a linear equation. Therefore, in orderto generate the linear mapping of PX to AVD_(s), a number of PX, AVD_(s)pairs are generated by measuring maximum aortic pulse pressure forvarying PX. The linear relationship is expressed by: AVD_(s)=M3 PX−M4milliseconds. In one embodiment, a calibration procedure was performedto generate a number of PX, AVD_(s) pairs, which are mapped and a bestline fit is performed to determine M3 and M4. In one embodiment, M1 isequal to 1.22 and M2 is equal to 132 milliseconds. Therefore, theAVD_(s) relationship is: AVD_(s)=1.22 PX−132 milliseconds. It is notedthat the coefficients may vary and that the estimated AVD_(s) may departfrom the actual optimum AVD_(s) by approximately 20 percent and continueto provide near optimal performance of the maximum stroke volume.Furthermore, the coefficients may vary slightly depending on the numberof samples taken in the calibration stage. Therefore, the coefficientsprovided herein may vary without departing from the present invention.

In one embodiment, the P-wave event is measured using a thresholddetection where the P-wave is determined to be 20% of the maximum P-waveamplitude. Other detection methods for the P-wave may be used withoutdeparting from the present system. The X event may be determined byseveral ways, including but not limited to: locating the point ofmaximum atrial pressure, Doppler measurements, and S4 components ofaccelerator measurements.

Other embodiments using different values for M3 and M4 are possiblewithout departing from the present system. Furthermore, other markersmay be used which are directly related to the PX time interval providedin one embodiment.

It is noted that any event which is relatively constant with respect tothe optimally timed V pacing signal (pacing using AVD_(s)) may be usedas a predictable event for use in the present system. In one embodiment,an event which is relatively constant is one which has a deviationbetween the lesser of 20 ms or 25 percent of the population mean.Therefore, other embodiments incorporating events not expresslymentioned herein may be used without departing from the present system.

Selection of Atrio-Ventricular Delay for Improved Contractility andStroke Volume

Depending on the condition of a heart and its disorders, optimalatrio-ventricular delay for maximum contractility may provide especiallynonoptimal stroke volume. Likewise, optimal atrio-ventricular delay formaximized stroke volume may result in nonoptimal contractility.Therefore, in order to provide a compromised atrio-ventricular delaywhich provides an approximately optimal atrio-ventricular delay for bothcontractility and stroke volume, AVD_(cs), it is desirable to have anatrio-ventricular delay which provides near optimal contractility andnear optimal stroke volume. The inventors of the present system deriveda relationship which provides a compromise between optimal contractilityand optimal stroke volume. In one embodiment, the optimizedatrio-ventricular delay, AVD_(cs), is a linear relationship in the PRtime interval, as follows: AVD_(cs)=K3 PR_(m)−K4 milliseconds. PR_(m) isa time interval measured from a right atrial sensing marker, P, to aright ventricular sensing marker, R_(m). In one embodiment, thecompromised AVD_(cs) is provided by determining AVD_(c) and AVD_(s) fora number of PR values and for a number of patients. Then a linearregression provides a best line fit for both contractility and strokevolume. In one embodiment, AVD_(cs) equals 0.5 PR_(m)−15 milliseconds,where AVD_(cs) is for pacing at least one ventricle, and where the timeinterval PR_(m) is measured from a right atrial sensing marker, P, to aright ventricular sensing marker, R_(m). In this embodiment, theresulting atrio-ventricular delay provides a left ventricular pressurechange within 90% of the optimal left ventricular pressure change duringsystole. Furthermore, this embodiment provides an aortic pulse pressurewhich is within 80% of the optimal aortic pulse pressure. It is notedthat the coefficients may vary and still provide a reasonableapproximation of AVD_(cs). For example, in one embodiment K3 may be inthe range from 0.4 to 0.6 and K2 may be in the range from 0 to 30 ms.Therefore, the present system offers flexibility in the selection ofcoefficients, and those provided are demonstrative and not an exclusiveset of coefficients.

In one embodiment, a left ventricular event is used to provide a timeinterval for calculation of AVD_(cs). In one case the LV event is the LVR-wave. The LV R-wave marker signal may also be used as an event. It isnoted that any event which is relatively constant with respect to thenear optimally timed V pacing signal may be used as a predictable eventfor use in the present system. In one embodiment, an event which isrelatively constant is one which has a deviation between the lesser of20 ms or 25 percent of the population mean. Therefore, other embodimentsincorporating events not expressly mentioned herein may be used withoutdeparting from the present system.

In one embodiment, the left ventricular R wave is used to develop arelationship between the PR interval (the time interval between a Pevent and an R event) and AVD_(cs). For a particular patient, theintrinsic PR interval is measured. Additionally, a sweep ofatrio-ventricular delays are applied to the pacing of the patient andLV+dp/dt and pulse pressure are measured for each differentatrio-ventricular delay. The LV+dp/dt data is plotted against anormalized value of the atrio-ventricular delay. Additionally, the pulsepressure is also plotted against a normalized value of theatrio-ventricular delay. In one embodiment, the atrio-ventricular delayis divided by PR-30 ms to normalize the delay. The tests are performedfor a number of additional patients and the normalized plots are mapped.Then an averaging of the various LV+dp/dt vs. normalizedatrio-ventricular delay data is performed. An averaging of the pulsepressure data vs. normalized atrio-ventricular delay data is alsoperformed. The atrio-ventricular delay (normalized value) at theLV+dp/dt curve peak is used as an optimal averaged atrio-ventriculardelay. The peak of the pulse pressure curve is also determined. In oneexample, the optimal averaged normalized atrio-ventricular delays forboth curves was determined to be approximately 0.50 times the normalizedPR time interval, or 0.50(PR−30) milliseconds.

In one study data was taken using a series of intermittent pacing (5pacing beats in every 15 sinus beats) from one of three sites (RV, LV,and BV) at one of five AV delays (equally spaced between 0 msec andPR-30 msec). Each pacing site/AV delay combination was repeated fivetimes in random order. Pressure and electrogram data were recorded fromthe ventricles. LV+dp/dt and PP were measured from LV and aorticpressure recordings on a beat-by-beat basis. For each paced beat, valuesof the LV+dp/dt and PP were compared to a preceding 6-beats-averagedsinus baseline. Then the response to pacing configuration was averaged.However, other measurements may be taken to obtain the requiredinformation.

Switchable Pacing Therapies

Any of the teachings provided herein may be employed in a variety ofcardiac devices, including implantable pacing devices. In oneembodiment, an implantable device also includes means for changing theventricular pacing to adjust for maximum contractility, maximum strokevolume or a compromise providing nearly optimal contractility and strokevolume. In such an embodiment, the pacing system contemplates the use ofall of the different optimal atrio-ventricular delays to adjust thetherapy to a cardiac patient. In one embodiment AVD_(cs) is used as adefault atrio-ventricular pacing delay, which may be maintained ormodified at a later time depending on the therapy required. For example,in one embodiment of the system, the pacing initiates with anatrio-ventricular delay equal to AVD_(cs). If at any time an optimalcontractility is required, the atrio-ventricular pace delay is changedto AVD_(c). Additionally, if at any time optimal stroke volume isrequired, the atrio-ventricular delay is changed to AVD_(s). Othervariations and combinations are possible without departing from thepresent invention. Furthermore, the switching of the pacing therapiesmay be provided by an external instruction, such as a programmer, or byan internally executing software for selecting the appropriate therapy.Other ways of switching between therapies may be encountered which donot depart from the present system.

CONCLUSION

The present pacing system may be employed in a variety of pacingdevices, including implantable pacing devices. The present system may beused for pacing one or more ventricles. A variety of pacing electrodeconfigurations may be employed without departing from the presentinvention including multiple pacing sites at a ventricle(s), providedthat the required electrical or mechanical events are monitored. Changesin the coefficients and order of methods provided herein may bepracticed accordingly without departing from the scope of the presentinvention.

1. A method, comprising: sensing a first cardiac event from a cardiaccycle; determining a second cardiac event from the cardiac cycle thathas an approximately constant timing relationship with respect to thefirst cardiac event; determining a first time interval between the firstcardiac event and the second cardiac event; and delivering a pacingpulse to approximately optimize a cardiac performance parameter being ameasure of systolic performance using a delay time interval referencedto the first cardiac event and calculated from the first time intervalbetween the first cardiac event and the second cardiac event by using apredetermined mathematical relationship of the first time interval to anapproximately optimal delay time interval for optimizing the cardiacperformance parameter.
 2. The method of claim 1, wherein determining asecond cardiac event from the cardiac cycle that has an approximatelyconstant timing relationship with respect to the first cardiac eventincludes determining a mechanical event that has an approximatelyconstant timing relationship with respect to the first cardiac event. 3.The method of claim 2, wherein: sensing a first cardiac event from acardiac cycle includes sensing an atrial electrical event (P); anddetermining a mechanical event that has an approximately constant timingrelationship with respect to the first cardiac event includesdetermining a mechanical event that has an approximately constant timingrelationship with respect to the atrial electrical event (P).
 4. Themethod of claim 3, wherein delivering a pacing pulse to approximatelyoptimize a cardiac performance parameter being a measure of systolicperformance using a delay time interval referenced to the first cardiacevent and determined from the first time interval between the firstcardiac event and the second cardiac event includes determining anatrio-ventricular delay (AVD_(c)) for optimizing contractility.
 5. Themethod of claim 4, wherein determining an AVD_(c) for optimizingcontractility includes forming a model that maps a PY interval to theAVD_(c), wherein the PY interval represents a time interval between theatrial electrical event (P) and a ventricular mechanical event (Y). 6.The method of claim 5, wherein Y indicates a beginning of ventricularcontraction.
 7. The method of claim 5, further comprising measuring Yfrom ventricular pressure.
 8. The method of claim 5, further comprisingmeasuring Y from wall motion.
 9. The method of claim 5, furthercomprising measuring Y using an accelerometer.
 10. The method of claim5, further comprising measuring Y using a phonogram.
 11. The method ofclaim 3, wherein delivering a pacing pulse for enhancing systolicperformance using a delay time interval determined from the first timeinterval between the first cardiac event and the second cardiac eventincludes determining an atrio-ventricular delay (ADV_(s)) for optimizingstroke volume.
 12. The method of claim 11, wherein determining a AVD_(s)for optimizing stroke volume includes forming a model that maps a PXinterval to the AVD_(s,) wherein the PX interval represents a timeinterval between the atrial electrical event (P) and a left atrialsystole peak event (X).
 13. The method of claim 12, wherein the leftatrial systole peak event (X) is measured by measuring LA pressure. 14.The method of claim 12, wherein the left atrial systole peak event (X)is measured by measuring LV pressure.
 15. The method of claim 3, whereindelivering a pacing pulse for enhancing systolic performance using adelay time interval referenced to the first cardiac event and determinedfrom the first time interval between the first cardiac event and thesecond cardiac event includes determining an atrio-ventricular delay(AVD_(cs)) for improved contractility and stroke volume.
 16. The methodof claim 1, wherein determining a second cardiac event from the cardiaccycle that has an approximately constant timing relationship withrespect to the first cardiac event includes determining an electricalevent that has an approximately constant timing relationship withrespect to the first cardiac event.
 17. The method of claim 16, wherein:sensing a first cardiac event from a cardiac cycle includes sensing anatrial electrical event (P); and determining an electrical event thathas an approximately constant timing relationship with respect to thefirst cardiac event includes determining a ventricular electrical event(Z) that has an approximately constant timing relationship with respectto the atrial electrical event (P).
 18. The method of claim 17, whereindelivering a pacing pulse for enhancing systolic performance using adelay time interval referenced to the first cardiac event and determinedfrom the first time interval between the first cardiac event and thesecond cardiac event includes determining an atrio-ventricular delay(AVD_(c)) for optimizing contractility.
 19. The method of claim 18,wherein determining an AVD_(c) for optimizing contractility includesforming a model that maps a PQ* interval to the AVD_(c), wherein the PQ*interval represents a time interval between the atrial electrical event(P) and a beginning of a QRS complex (Q*).
 20. The method of claim 18,wherein determining an AVD_(c) for optimizing contractility includesforming a model that maps a PR interval to the AVD_(c), wherein the PRinterval represents a time interval between the atrial electrical event(P) and a peak of ventricular depolarization (R).
 21. The method ofclaim 17, wherein delivering a pacing pulse for enhancing systolicperformance using a delay time interval referenced to the first cardiacevent and determined from the first time interval between the firstcardiac event and the second cardiac event includes determining anatrio-ventricular delay (AVD_(s)) for optimizing stroke volume.
 22. Themethod of claim 1, wherein the predetermined mathematical relationshipis determined by: selecting a cardiac reference event which is used totime a pacing pulse and which repeats every cardiac cycle as the firstcardiac event; selecting a cardiac systolic event that has a fixed timerelationship with systole of each cardiac cycle as the second cardiacevent; measuring the first time interval between the cardiac referenceevent and the cardiac systolic event in an unpaced condition;ascertaining an optimal pacing delay between the reference event and thedelivery of a pacing pulse for optimizing the cardiac performanceparameter; collecting first time intervals and optimal pacing delays fora number of patients; and deriving a mathematical relationship betweenthe first time intervals and the optimal pacing delays.
 23. The methodof claim 22, wherein the cardiac performance parameter includescontractility.
 24. The method of claim 22, wherein the cardiacperformance parameter includes stroke volume.
 25. The method of claim22, wherein selecting a cardiac reference event which is used to time apacing pulse and which repeats every cardiac cycle includes selecting anelectrical cardiac event that repeats every cycle.
 26. The method ofclaim 22, wherein selecting a cardiac reference event which is used totime a pacing pulse and which repeats every cardiac cycle includesselecting a mechanical cardiac event that repeats every cycle.
 27. Themethod of claim 22, wherein selecting a cardiac systolic event that hasa fixed time relationship with systole of each cardiac cycle includesselecting an electrical cardiac event that has a fixed time relationshipwith systole of each cardiac cycle.
 28. The method of claim 22, whereinselecting a cardiac variable event that has a fixed time relationshipwith systole of each cardiac cycle includes selecting a mechanicalcardiac event that has a fixed time relationship with systole of eachcardiac cycle.